Project Summary/Abstract. A clinical need exists for better osteoporosis treatments since only one anabolic therapy (truncated recombinant human parathyroid hormone 1-34, teriparatide/Forteo(R)) is commercially available. Bears possess the unique ability to prevent bone loss during physical inactivity (hibernation) by maintaining balanced bone remodeling;the biological processes behind this phenomenon are likely governed by endogenous parathyroid hormone (PTH), since serum PTH levels are correlated with the bone formation marker osteocalcin in hibernating and active bears. Thus, our goal is to investigate the anabolic effects of Black Bear (BB)- PTH 1-84 to aid in the development of a more effective anabolic treatment for osteoporosis. It is possible to up-regulate anabolic pathways in bone cells by altering the amino acid sequence of PTH. BB-PTH 1-84 has nine differences in its amino acid sequence compared to full length human PTH. Thus, BB-PTH 1-84 may promote a greater anabolic response in bone than human PTH by decreasing osteoblast apoptosis and increasing bone matrix production by altering gene expression. In Phase I work we recombinantly produced BB-PTH 1-84 and found it is significantly more potent at increasing bone mass and strength in healthy male mice. In the Phase II work we will perform a dose-response study in ovariectomized mice to evaluate the efficacy of bear PTH 1-84 at reversing ovariectomy induced bone loss. We will also treat human osteoblastic cells with human PTH 1-84 and BB-PTH 1-84 to compare their abilities to activate anabolic bone cell responses by activating the human PTH receptor. Importantly, non-GLP and GLP pathology/toxicology studies will be performed with Phase II STTR funding in order to enable the Company to file an IND with the FDA to initiate future Phase I/II clinical studies in patients with documented osteoporosis. PUBLIC HEALTH RELEVANCE: Project Narrative: Improved drug therapies are needed to treat the approximately 44 million Americans affected by osteoporosis. Bears uniquely prevent osteoporosis during physical inactivity (hibernation) through biological processes regulated by parathyroid hormone (PTH). Injections of human PTH are currently used to rebuild bone in severely osteoporotic patients, but due to its different amino acid sequence, BB-PTH 1-84 may elicit greater bone formation than human PTH, and therefore may be a more effective treatment for human osteoporosis.